The existence of central as well as peripheral multiple opioid receptors has been demonstrated with the use of selective agonists. It was also found that these opioid receptors interact in a highly selective fashion with these opioids and mediate their major pharmacological effects. The purpose of this research renewal proposal is to further characterize the CNS opioid receptors (mu, kappa, sigma, and delta) by studying effects of the selective agonists on EEG, EEG power spectra, and behavior of adult female Sprague-Dawley rats bearing chronic EEG-EMG electrodes and i.v. cannulae. Prototype agonists for the mu, kappa, sigma, and delta receptors are represented by morphine, ketocyclazocine, SKF-10,047, and D-ala2-D-leu5-enkephalin, respectively (Martin et al, 1976; Lord et al, 1977). We intend to study the acute and chronic EEG and EEG spectral effects of these agonists; to define the extent of involvement of the different receptors in producing tolerance; to assess the degree of cross-tolerance between these selective opioid agonists; to define the relative degree of physical dependence produced after chronic administration of these opioids by studying spontaneous and naloxone-induced EEG and behavioral changes upon withdrawal; and to characterize long-term effects of acute and chronic exposure of rats to these opioids by assessing the EEG and behavioral responses to opioid challenges in these rats for a period up to twelve months after the initial exposures to the opioid. We plan to further characterize the agonistic properties of the new mixed agonist-antagonist analgesics, butorphanol and nalbuphine, by comparing their EEG effects with those produced by selective mu, kappa, sigma, and delta opioid agonists. We also plan to assess the degree of possible substitution of these opioids for morphine in dependent rats self-administering morphine and to avail these opioids for self-administration in morphine post-addict rats. These self-administration studies will demonstrate possible abuse potential related to the respective opioid receptor population stimulated. Our proposed in vivo studies of drug-receptor interactions using selective opioid agonists and studying electroencephalographic effects should allow further definition of the relative roles of the different CNS opioid receptor population stimulated. Our proposed in vivo studies of drug-receptor interactions using selective opioid agonists and studying electroencephalographic effects should allow further definition of the relative roles of the different CNS opioid receptor populations in the phenomenon of drug dependence.